Cancer Immunology and Immune suppression Flashcards
What is the evidence of an immune response to cancer?
immune suppression increases tumour incidence; inflammatory immune responses can also promote tumour incidence; presence of immune response associated with prognosis
Give examples of inflammatory immune responses promoting tumour incidence?
H.pylori and stomach cancer; hep B and liver cancer; pancreatitis and pancreatic cancer
What cytokines promote tumour clearance?
IFNy and IL-2
How does advanced cancer perpetuate immune dysfunction?
cell heterogeneity; TCR dysfunction; desnity of antigen on the tumour cells may be lower than the threshold for recognition; host system may be too overwhlemed; defective APCs; MDSC
How does cancer cause TCR dysfunction?
change in quality (phosphorylation); change in quantitty (proteolysis) due to tumour microenvironment
Which cells is TCR dysfunction in cancer first seen in?
TILs then in PBMCs
How does cancer overwhelm the immune system?
continuous shedding of tumour associated antigen may induce tolerance; local Th2 response is stimulated; T cells less IL2 responsive
How do cancers cause defective APCs?
lack of MHC-I expression of B7; lack of costimulation- anergy ; VEGF immunsuppresses APCs
What do monocytic MDSCs differentiate to in tumour sites?
tumour associated macrophages and inflammatory DCs
What are the 2 types of MDSC?
monocytic type and polymorphonuclear type
What attracts monocytic MDSCs to the tumour site?
chemokines CCL2 and CCL5 and grwoth factor CSF-1
What controls the differentiation of TAMs?
HIF-1a increase and STAT3 decrease
What can TAMs differentiate into
M1 and M2 types
What is the effect of both M1 and M2-like TAMs?
suppression of T cells
How do M1-like TAMs inhibit T cell function?
NO
How do M2-like TAMs inhibit T cell function?
arginase 1
What does the functional outcome of the MDSC depend on/
tumour microenviroment
When are MDSCs formed?
in the context of cancer, normally become monocytes or PBMCs
What factor in the cancer microenvironment helps stimulate formation of TAMs?
hypoxia and VEGF
What are the features of tumour mediated immune evasion?
loss of expression of mutation of tumour antigens; loss of antigen processing and presentation-MHC-1; expression of immunosuppressive factors; activation of Tregs; expression of decoys- soluble circulating tumour antigens; clonal exhaustion; tolerane induced by continuous shedding of TAAs; expression of PD-L1; loss of Fas;; intrisinsic resistance to apoptosis
What are the authors of the hallmarks of cancer?
Hanahan and Weinberg
What are hte hallmarks of cancer?
sustained proliferative signalling; resisting cell death; evading growth suppressors; activating invasion and metastasis; enabling replicative immortality; inducing angiogenesis; avoiding immune destruction
What is the effect of APCs producing IDO and arginase?
inhibits CD3 function on CTLs
What is the effect of IL-10 and TGFb produced by APCs?
induces Tregs which inhibit CTLs
What are hte major mechanisms by which CTLs kill target cells?
perforin/granzyme and Fas/FasL
How does the tumour have intrinsic resistance to apoptosis?
upregulation of anti-apoptotic proteins Bcl2, survivin
What factors barrier the activation; proliferation and survival of naive tumour specific T cells?
CTLA-4; Tregs; TGFb; IL-10; lack of TLR signals ; lack of yc cytokines
What prevents the activated tumour specific T cell migrating to the tumour site?
lack of chemokine expression by tyumours; lack of chemokine receptors on T cells
What inhibits the effector functions of tumour-specific T cells?
Tregs; PD-L1; TGFb; IL-10; IDO; arginase; iNOD; VEGF
What suggests taht ovarian tumours may be amenable to immune attack?
high numbers of TILs associated with better prognosis; express tumour antigens e.g CA-125
How do ovarian cacners suppress the immune repsonse?
high Tregs associated with increased resistance to chemo and decreased survival; icnreased expression of PDl1; lipids in ascites can suppress NK activation; TNFa production generates an autocrine tumour-promoting network
What is found on the intracellular domain of PD-1?
ITSM and ITIMs
What binds to ITSM on intracellular domain of PD-1?
SHP-2
What happens when PD-1 is activated?
SHP2 is able to dephosphorylate proximal signalling kinases of the TCR
Which cells express PD-1?
activated T and B cells; macropahges
What scientists were invovled in checkpoint inhibition mAbs?
Allison- CTLA4 and Honjo- PD-1
What does engagement of PD-1 result in?
T cell anergy
What was the recent clinical success of anti-PD1?
complete of partial response to different types of cancer- melanoma; renal cell carcinoma
What is the name for the anti-PD1?
nivolumab
What represents a challenge in the anti-PD1 therapy?
there is no correlation between tumour PD-L1 expression and response to therapy- unknown why some patients respond and others don’t
What is the name for the anti-CTLA4?
ipilumumab
What is nivolumab approved for?
melanoma and small cell lung cancer
What is ipilimumab approved for?
advanced melanoma
What is the efficacy of ipilumamab?
aroudn 4 months increase in overall survival
What is the difference between anti-CTLA4 and anti-PD1/PDL1?
anti-CTLA4 has higher increase in overall suvival but there are higher toxicities
